Evaluation of candidate International Standards for meningococcal capsular polysaccharide groups W and Y.

Two candidate International Standards for meningococcal capsular group W and Y (MenW and MenY, respectively) polysaccharides were assessed for their suitability as quantitative standards in various physicochemical assays. The study was designed to evaluate the intended purpose of these standards, namely, to standardize the quantification of the respective polysaccharide content in meningococcal polysaccharide and conjugate vaccines and their intermediate components. Twelve laboratories from eleven different countries participated in the collaborative study of candidate preparations for International Standards for MenW and MenY polysaccharide (coded 16/152 and 16/206, respectively). Unitage was assigned using the Resorcinol assay. Our proposals, on the basis of data from the Resorcinol assay were: 1) candidate standard for MenW polysaccharide (16/152) to be assigned a content of 1.015 ± 0.071 mg MenW polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.13, corresponding to a 95 % level of confidence) and 2) candidate standard for MenY polysaccharide (16/206) be assigned a content of 0.958 ± 0.076 mg MenY polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.26, corresponding to a 95 % level of confidence). The amount of polysaccharide per ampoule remained consistent under all stability conditions over a 36-month period.

Saccharide dosage content of meningococcal polysaccharide conjugate vaccines determined using WHO International Standards for serogroup A, C, W, Y and X polysaccharides.

Potency of meningococcal polysaccharide-protein conjugate vaccines relies on the polysaccharide content to prevent meningitis. NIBSC, as the official national control laboratory in UK, analysed ten different mono- and multi-meningococcal conjugate vaccines, using established International Standards for meningococcal serogroups A, C, W, Y and X, by resorcinol or HPAEC-PAD assay. Most saccharide contents were within ±20% of their claimed content for licensure with taking different O-acetylation levels into consideration, with only MenC content in two vaccines below (by 60% and 54%) the labelled value, however, previous study showed different dosage was not necessarily correlated to the immunogenicity of those vaccines. This study demonstrated the use of International Standards to quantify saccharide content in polysaccharide-based vaccines with different percentage of O-acetylation. These International Standards are suitable to serve as either quantitative standard or calibrator of in-house standards, with supplied stability data.

Evaluation of candidate international standards for meningococcal serogroups A and X polysaccharide.

Polysaccharide (PS) based meningococcal vaccines are primarily evaluated by physicochemical methods to ensure batches are consistently manufactured. As PS content is determined by different methods across numerous laboratories, there is a need for International Standards (IS) to calibrate the assays. Following the successful introduction of the WHO Meningococcal group C (MenC) IS in 2011, NIBSC initiated projects to prepare similar standards for groups A, W, Y and X (MenA/W/Y/X) to standardise all meningococcal- PS based vaccines. On the basis of results from a collaborative study to evaluate preparations of MenA and MenX PS, both were established by the WHO Expert Committee on Biological Standardization in Oct 2015 as; the First WHO International Standard for the Meningococcal Group A polysaccharide with a content of 0.845 ± 0.043 mg MenA PS per ampoule (expanded uncertainty with coverage factor of k=2.45 corresponding to a 95% level of confidence); the First WHO International Standard for the Meningococcal Group X polysaccharide with a content of 0.776 ± 0.089 mg MenX PS per ampoule (expanded uncertainty with coverage factor of k=2.45), as determined by quantitative NMR. The standards are available from NIBSC, who act as guardians and distributors of the material under the auspices of WHO.

10 Practice Recommendations in Adult Vaccination Administration.

Although the provision of immunoprophylaxis to children has become routine in the practice of pediatric preventive care, the same is not true in adult primary care. Contributing to this problem is a lack of knowledge among providers of adult preventive care. This review aimed to bolster providers' understanding of adult vaccinations by highlighting changes in vaccination recommendations and addressing common knowledge gaps. This is not a comprehensive list of vaccination recommendations, but rather the "top 10" common misconceptions, advancements, and updates we have found in our reading of the vaccination literature and in our own experience in a training institution.

Regulatory Pathways That Facilitated Timely Registration of a New Group A Meningococcal Conjugate Vaccine for Africa's Meningitis Belt Countries.

BACKGROUND: Through its normative and public health leadership roles, the World Health Organization (WHO) plays a key role in the availability of vaccine products in low-and middle-income countries. The recent introduction of a new group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), in Africa exemplifies this process. WHO requires that any new vaccine to be introduced in countries for public health reasons and supplied through United Nations centralized mechanisms be licensed by the national regulatory agency (NRA) in the producing country, then prequalified and given a marketing authorization in the user countries. METHODS: PsA-TT was manufactured by the Serum Institute of India, Ltd (SIIL), which submitted a license application in April 2009 to the Drug Controller General of India (DCGI), the Indian NRA responsible for licensing vaccines. WHO encouraged the DCGI to establish a collaboration with Health Canada's Centre for Vaccine Evaluation for the review. Through this collaborative effort, registration was facilitated and in December 2009 an export license was granted to SIIL, which subsequently submitted an application for WHO prequalification. RESULTS: Given the importance of the vaccine, WHO "fast tracked" the prequalification review, and after a detailed review and site visit, WHO prequalification was granted to PsA-TT in June 2010. Country use of the new vaccine could not occur until the vaccine was a registered product in each country seeking its use. WHO facilitated country reviews by conducting regulatory training exercises (in French and English) for country NRA staff, which used the PsA-TT registration as a case study. CONCLUSIONS: PsA-TT was gradually registered in African countries as vaccine introduction proceeded. The regulatory pathway for this new group A meningococcal conjugate vaccine proved to be a useful training opportunity both in India and Africa, because the availability of the vaccine was a high African public health priority, as well as for WHO as a case study to facilitate registration of vaccines based on reliance on other regulatory bodies.

WHO/Health Canada meeting on regulatory considerations for evaluation and licensing of new meningococcal Group B vaccines, Ottawa, Canada, 3-4 October 2011.

Serogroup B Neisseria meningitides (MenB) is a significant cause of endemic and epidemic outbreaks of the disease worldwide. Although polysaccharide and conjugate vaccines are available against other meningococcal serogroups, the poor immunogenicity of MenB polysaccharide has led to the development of protein-based vaccines. However, the diversity and antigenic variability of MenB strains has been a major challenge. Recently a new generation of MenB vaccines that contain conserved antigens has been developed to provide broader coverage and they are in an advanced stage of development and regulatory consideration. In October 2011, the World Health Organization and Health Canada jointly organized a consultation on regulatory considerations for the evaluation and licensing of new MenB vaccines. The aim was to seek consensus on key regulatory issues relevant to the evaluation of candidate MenB vaccines and on approaches to the standardisation of in vitro assays used in the evaluation process. Participants agreed that functional antibodies as measured in the Serum Bactericidal Activity (SBA) assay could be used to evaluate MenB vaccine efficacy and ways of improving assay standardization proposed. Approaches to bridging SBA data to large collections of strains in order to give an indication of the prospective breadth of vaccine coverage were discussed.

Evaluation of a candidate International Standard for Meningococcal Group C polysaccharide.

Meningococcal group C (MenC) plain polysaccharide (PS) and conjugate vaccines are primarily evaluated by physicochemical methods to ensure that batches are consistently manufactured. As different assays are employed to quantify the MenC PS content of final formulations and bulk intermediaries, there is a need for an International MenC PS Standard to calibrate internal references used in the different laboratories. Twelve laboratories from nine different countries participated in a collaborative study to determine the MenC PS content of a candidate International Standard MenC PS preparation (08/214) and to assess its suitability. On the basis of the results from this study the candidate standard 08/214 was established as an International Standard for the quantification of MenC PS content in vaccines and components. It has a content of 1.192 ± 0.192 mg MenC PS/ampoule (expanded uncertainty with coverage factor of k = 2.365 corresponding to a 95% level of confidence), as determined by the resorcinol assays carried out by eight of the participating laboratories. The standard is available from The National Institute of Biological Standards and Control who act as guardians and distributors of the material under the auspices of WHO.

WHO Expert Committee on biological standardization.

This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the attention of the Committee and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, and endocrinological substances. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains WHO recommendations and guidelines on human papillomavirus vaccines; meningococcal A conjugate vaccines; and stability evaluation of vaccines. Also included are a list of recommendations, guidelines and other documents for biological substances used in medicine, and of international standards and reference reagent for biological substances.

[Meningococcemia and meningitis due to Neisseria meningitidis W135 developed in two cases vaccinated with bivalent (A/C) meningococcal vaccine]. / Bivalan (A/C) meningokok asisi ile asilanmis iki olguda Neisseria meningitidis W135'e bagli gelisen meningokoksemi ve menenjit.

Meningococcal infections may develop as episodic or endemic cases particularly among children attending day-care centers, boarding schools or among military personnel. Bivalent (A/C) meningococcal vaccine is applied to all new military stuff since 1993 in Turkey. In this report two cases of meningococcemia and meningitis, developed in two soldiers vaccinated with meningococcal vaccine, were presented. The first case was a 21 years old male patient who was admitted to the emergency service with the complaints of high fever, headache, fatigue and vomiting. He was conscious, cooperative and oriented with normal neurological findings. Maculopapular exanthems were detected at the lower extremities. The patient was hospitalized with the initial diagnosis of sepsis or meningococcemia and empirical treatment was initiated with ceftriaxone and dexamethasone. Cerebrospinal fluid (CSF) examination yielded 10 cells/mm3 (lymphocytes) with normal CSF biochemical parameters. A few hours later skin rashes spread over the body rapidly, the symptoms got worse, confusion, disorientation and disorientation developed, and the patient died due to cardiac and respiratory arrest at the seventh hour of his admission. The second case was also a 21 years old male patient who was admitted to the hospital with the complaints of fever, headache, painful urination, confusion and agitation. He was initially diagnosed as acute bacterial meningitis due to clinical (stiff neck, positive Kernig and Brudzinsky signs) and CSF (8000 cells/mm3; 80% polymorphonuclear leukocytes, increased protein and decreased glucose levels) findings. Empirical antibiotic therapy with ceftriaxone was initiated and continued for 14 days. The patient was discharged with complete cure and no complication was detected in his follow-up visit after two months. The first case had an history of vaccination with bivalent (A/C) meningococcal vaccine three months ago and the second case had been vaccinated one month ago. The bacteria isolated from the blood culture of the first case and the CFS culture of the second case, were identified as Neisseria meningitidis by conventional and API NH system (BioMerieux, France). The isolates were serogrouped as W135 by slide agglutination method (Difco, USA), and both were found to be susceptible to penicillin and ceftriaxone. As far as the last decade's literature and these two cases were considered, it might be concluded that N.meningitidis W135 strains which were not included in the current bivalent meningococcal vaccine, gained endemic potential in Turkey. Since N.meningitidis W135 strains may lead to serious diseases, vaccination of the risk population with the conjugate tetravalent meningococcal vaccine (A/C/Y/W135) should be taken into consideration in Turkey.

Recurrent meningococcal meningitis with complement 6 (C6) deficiency: A case report.

RATIONALE: Late complement deficiency increases susceptibility to meningococcal disease and recurrent infections. In Korea, 5 case reports have described meningococcal disease with complement deficiency. However, C6 deficiency has not been described previously. PATIENT CONCERNS: A 21-year-old police trainee presented with recurrent meningococcal meningitis. He was housed in communal living quarters until 20 days before the initial symptom onset. DIAGNOSIS: He was diagnosed with meningococcal meningitis with C6 deficiency. INTERVENTIONS: He was treated with intravenous ceftriaxone. An additional dose of quadrivalent meningococcal conjugate vaccine was administered after discharge. OUTCOMES: He was discharged without complications. LESSONS: Screening for complement deficiency is necessary in patients with a history of recurrent meningococcal infections to provide appropriate care and prevent recurrent infections.

Meningococcal and pneumococcal carriage in Hajj pilgrims: findings of a randomized controlled trial.

BACKGROUND: Intense congestion during the Hajj pilgrimage amplifies the risk of meningococcal carriage and disease, and there have been many meningococcal outbreaks reported amongst pilgrims. Thus, a strict vaccination policy is enforced by the host country and either polysaccharide or conjugate quadrivalent meningococcal vaccines are mandatory. However, unlike conjugate vaccines, the polysaccharide vaccine is not thought to reduce pharyngeal carriage of meningococci. METHODS: A single-blinded, randomized, controlled trial amongst pilgrims from Saudi Arabia and Australia during the Hajj seasons of 2016-2017 was conducted to compare MenACWY-Conjugate vaccine with MenACWY-Polysaccharide vaccine, to determine if the conjugate vaccine is more effective in reducing asymptomatic carriage of meningococci, and whether the effect may be long-standing. Oropharyngeal swabs were obtained pre-, immediately post- and 6-11 months following completion of Hajj and tested for the presence of meningococci. RESULTS: Amongst 2000 individuals approached, only 1146 participants aged 18-91 (mean 37.6) years agreed to participate and were randomized to receive either the polysaccharide (n = 561) or the conjugate (n = 561) vaccine, 60.8% were male, and 93.5% were from Saudi Arabia. Amongst oropharyngeal swabs obtained before Hajj, only two (0.2%) tested positive for Neisseria meningitidis. Similarly, meningococci were identified in only one sample at each of the post-Hajj and late follow-up visits. None of the carriage isolates were amongst the serogroups covered by the vaccines. A post hoc analysis of the third swabs revealed that 22.4% of all participants (50/223) were positive for Streptococcus pneumoniae nucleic acid. CONCLUSION: The low overall carriage rate of meningococci found amongst Hajj pilgrims in 2016 and 2017 demonstrates a successful vaccination policy, but neither supports nor refutes the superiority of meningococcal conjugate ACWY vaccine over the polysaccharide vaccine against carriage. Although an association could not be established in this study, molecular epidemiology would help to establish the role of Hajj in facilitating transmission of pneumococci and inform vaccination policy.

Control Strategy Approach for a Well-Characterized Vaccine Drug Product.

Trumenba (MenB-FHbp; bivalent rLP2086), the first meningococcal serogroup B vaccine approved in the United States and subsequently approved in Europe, Canada, and Australia, is well-characterized. Pfizer devised a control strategy approach by using a simplified control strategy wheel for Trumenba based on International Council for Harmonisation (ICH) Q8 (R2), Q9, Q10, and Q11 guidelines, which provide complementary guidance on pharmaceutical development, quality risk management, quality systems, and development and manufacture of drug substances, respectively. These guidelines ensure product quality using a scientific and risk-based approach. Trumenba contains two factor H binding proteins (FHbps), one from each of the two FHbp subfamilies (A and B), adsorbed onto aluminum phosphate. Trumenba manufacturing processes are complicated by the recombinant protein expression of Subfamily A and B proteins and the nature of the drug product (suspension in syringes); the latter also introduces challenges in controlling product critical quality attributes during the development process. In such complex systems, the control strategy is critical to ensuring consistent desired product quality; it also supports the regulatory requirement of continued improvement through continuous process verification and aids regulatory filing. This article describes Pfizer's approach toward robust control strategy development, built on product and process understanding, and links control strategy to regulatory document sections and flow of controls. Specifically, an approach is presented on product quality attribute criticality determination based on safety and efficacy and on an understanding of process parameter criticality. This was achieved by studying the impact of the approach on product quality attributes to define process parameter and in-process controls. This approach is further explained through Trumenba case studies, highlighting specific quality attributes and the associated controls implemented, and provides a holistic view of controls employed for both drug substance and drug product.

Routine Childhood Vaccines Given From 1 through 18 Years of Age.

In addition to the vaccines due in the first year of life, the US Advisory Committee on Immunization Practices recommends that children continue to receive vaccines regularly against a variety of infectious diseases. Starting at 12 to 15 months of life, these include the two-dose measles-mumps-rubella vaccine series and the two-dose varicella vaccine series. Also in the second year of life, infants should begin the two-dose hepatitis A vaccine series and complete the Haemophilus influenzae type B vaccine series as well as the pneumococcal conjugate vaccine series. Before 19 months of life, infants should receive the third dose of the poliovirus vaccine and the fourth dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The final doses of poliovirus and tetanus-diphtheria-acellular pertussis vaccines are both due at 4 to 6 years of life. Before each influenza season, every child should receive the influenza vaccine. Those less than 9 years of age who previously received less than two doses need two doses a month apart. At 11 to 12 years of life, all should get two doses of the human papillomavirus vaccine, the adolescent/adult version of the tetanus-diphtheria-acellular pertussis vaccine, and begin a two-dose series of meningococcal ACWY vaccine. Each of these vaccines is due when the vaccine works to protect against both an immediate risk as well as to provide long-term protection. Each vaccine-preventable disease varies in terms of the nature of exposure, the form of the morbidity, the risk of mortality, and potential to prevent or ameliorate its harm.

Prophylactic amoxicillin for the prevention of meningococcal infection in infants with atypical hemolytic uremic syndrome under treatment with eculizumab: a report of two cases.

Eculizumab, a humanized monoclonal antibody to complement C5, is a therapeutic drug for atypical hemolytic-uremic syndrome (aHUS) that inhibits the terminal pathway of complement. Patients on eculizumab therapy may become more susceptible to infection with capsule-forming bacteria, including meningococci. Therefore, meningococcal vaccination is required for patients who are on eculizumab therapy. However, the means to prevent meningococcal infection in infants who cannot be vaccinated with the available meningococcal vaccine have not yet been established internationally. In two infants with aHUS at 4-5 months after birth, prophylactic oral amoxicillin was administered, and meningococcal infection was not detected during the period between the initiation of eculizumab therapy and the administration of meningococcal vaccine. Neither adverse events related to amoxicillin nor thrombotic microangiopathy occurred during the treatment. Thus, oral administration of amoxicillin may be effective for preventing meningococcal infection under treatment with eculizumab in infants who have not received meningococcal vaccination.

The Hajj 2019 Vaccine Requirements and Possible New Challenges.

Each year millions of pilgrims perform the annual Hajj from more than 180 countries around the world. This is one of the largest mass gathering events and may result in the occurrence and spread of infectious diseases. As such, there are mandatory vaccinations for the pilgrims such as meningococcal vaccines. The 2019 annual Hajj will take place during August 8-13, 2019. Thus, we review the recommended and mandated vaccinations for the 2019 Hajj and Umrah. The mandatory vaccines required to secure the visa include the quadrivalent meningococcal vaccine for all pilgrims, while yellow fever, and poliomyelitis vaccines are required for pilgrims coming from countries endemic or with disease activity. The recommended vaccines are influenza, pneumococcal, in addition to full compliance with basic vaccines for all pilgrims against diphtheria, tetanus, pertussis, polio, measles, and mumps. It is imperative to continue surveillance for the spread of antimicrobial resistance and occurrence of all infectious diseases causing outbreaks across the globe in the last year, like Zika virus, MDR-Typhoid, Nipah, Ebola, cholera, chikungunya and Middle East Respiratory Syndrome Coronavirus.

Monoclonal Antibodies Against the Capsular Polysaccharides A, C, Y, W, and X of Neisseria meningitidis: A Platform for the Quality Control of Meningococcal Vaccines.

Vaccination has reduced morbidity and mortality of many diseases that previously caused devastating epidemics and deaths globally. Vaccines as a biological product may contain microorganisms or their derivatives. This aspect together with the fact that they are administered to healthy individuals (mainly children) means that approximately 70% of vaccines development time is dedicated to quality control. Monoclonal antibodies (MAbs) have become essential analytical tools for application in ELISAs, Western and Dot blotting, immunoprecipitation, and flow cytometric assays that ensure the quality control of vaccines. The aim of this work is to present a review of the methods used to obtain a platform of MAbs against Neisseria meningitidis polysaccharide antigens to use as an analytical tool for quality control of anti-meningococcal polysaccharide (Ps) vaccines. The MAbs obtained are used in five sandwich ELISAs developed for Ps quantification. The assays showed good reproducibility and repeatability, with quantitation and detection limits below 1 ng/mL. Dot Blot, as the Identity test of the Ps vaccine, was carried out to positively identify licensed and experimental vaccines. All assays described are suitable for the screening of multiple vaccine samples and could be useful for monitoring lot-to-lot consistency and stability.

Mass chemoprophylaxis for control of outbreaks of meningococcal disease.

Although vaccination is the main strategy used to control meningococcal disease outbreaks, mass chemoprophylaxis has also been used as an immediate response to outbreaks, either to supplement vaccination or when vaccination is not possible. However, public health guidelines regarding the use of mass chemoprophylaxis for outbreak control vary by country, partly because the impact of mass chemoprophylaxis on the course of an individual outbreak is difficult to assess. We have reviewed data for the use of mass chemoprophylaxis during 33 outbreaks that occurred both in military populations and in communities and non-military organisations. In most outbreaks, no additional cases of meningococcal disease occurred after mass chemoprophylaxis, or cases occurred only in individuals who had not received prophylaxis. A delay of several weeks was common before cases occurred among prophylaxis recipients. Overall, the outbreak reports that we reviewed suggest that mass chemoprophylaxis might provide temporary protection to chemoprophylaxis recipients during outbreaks.

Impact of pneumococcal conjugate vaccine on the prevention of invasive pneumococcal diseases.

OBJECTIVES: To evaluate the impact of heptavalent pneumococcal conjugate vaccine in invasive pneumococcal diseases in the United States, and to analyze the potential impact of this vaccine in Brazil. SOURCES OF DATA: MEDLINE, LILACS, Cochrane Database Reviews, as well as the websites of the Centers for Disease Control and Prevention (CDC), Brazilian Ministry of Health and Centro de Vigilância Epidemiológica do Estado de São Paulo from January 2000 to January 2006. Articles retrieved with the keywords Streptococcus pneumoniae, pneumococcal diseases, conjugate vaccine, antimicrobial resistance and meningitis were reviewed. SUMMARY OF THE FINDINGS: The introduction of heptavalent pneumococcal conjugate vaccine caused a dramatic reduction in the incidence of invasive pneumococcal diseases in American children, reduced antibiotic use and the number of medical visits due to otitis media and pneumonia by children. The incidence of invasive pneumococcal diseases caused by resistant strains declined in immunized children, adults and elderly individuals. In Brazil, the mortality rate of pneumococcal meningitis is very high and the resistance to antibiotics has increased over the last 5 years. CONCLUSIONS: Heptavalent pneumococcal conjugate vaccine can benefit not only children, but the entire community and should be included in the Brazilian routine immunization schedule.

[Specific antibodies and their role in the formation of antidiphtheria immunity].

In human sera, studied with the use of the enzyme immunoassay, antidiphtheria postvaccinal antitoxic IgG and naturally acquired antibacterial IgG, IgM and IgA were detected. In the blood of children and adults aged up to 50 years antitoxic IgG were present at normal and high concentrations. In 50% of children antibacterial IgA were absent, while specific antibacterial IgM could be found at high concentrations. Changes in the content of antibacterial antibodies of different classes in sera were observed with age. More than 90% of adults had antibacterial IgA and IgG at normal and hig concentrations, while the level of IgM decreased. Under the influence of ecological, social, anthropogenic and other environmental factors the optimum levels of specific antibodies were replaced by anomalous ones, which led to an increased number of persons susceptible to diphtheria infection and in the intensity of the circulation of the infective agent. The deficiency of antidiphtheria antibacterial antibodies in the blood determined the necessity of correcting immunity by means of not only toxoid, but also bacterial antigens.